Vaccination with malaria irradiated sporozoites (irr-spz) represents one of the most promising means to prevent the development of pre-erythrocytic stages of human Plasmodia and therefore of preventing malaria disease. Studies conducted in human and animal models have reproducibly demonstrated that this vaccination strategy consistently induces solid sterile protection. The purpose of this research is to standardize a Plasmodium vivax irr-spz vaccine model in human volunteers. This general objective will be approached by addressing the following specific aims: 1) To conduct proof- of-principle studies on the protective efficacy of P. vivax irr spz vaccination in human volunteers;and 2) To evaluate the immune responses in all study participants and search for immune correlates of protection. Studies will involve P. vivax-infected individuals serving as parasite donors and both Duffy+ (Fy+) and Fy- healthy volunteers that will be serially immunized (10-15 times) with irradiated or non- irradiated P. vivax infected mosquitoes. A total of 24 malaria naive volunteers will be allocated to four groups (A-D) of six volunteers each. Group A (Fy+) and group B (Fy-) volunteers will be vaccinated with irr- spz. Group C (Fy- volunteers) will be vaccinated with live spz. After the vaccination protocol is completed, all volunteers, including a control group D (not vaccinated) will be challenged by the bite of infected mosquitoes. Volunteers will be closely followed and development of patent infection will be assessed by thick blood smear to assess the protective efficacy of the vaccination. Infected volunteers will be immediately treated with standard antimalarial therapy. Specific immune response to P. vivax pre-erythrocytic antigens including whole parasites will be studied by measuring B cell, CD4+ and CD8+ T cell responses as well as Th1/Th2 cytokine production. Reagents (sera/cells) collected during this study will be used to screen for novel genes/antigens with potential for vaccine development. Immunological analyses are expected to allow the identification of immune correlates of protection. The proposed experiments will be performed at the Malaria Vaccine and Drug Development Center (MVDC) in Colombia, with support from US and European collaborators. The participating teams combine unique capabilities and physical facilities for the conduct of the proposed clinical trial and immunological studies as well as to contribute to the development of a P. vivax malaria vaccine. PUBLIC HEALTH RELEVANCE: Vaccines represent the most cost-effective measure to control transmissible diseases. Therefore, a malaria vaccine that prevents parasite transmission from mosquito to human or its development in human beings would become a valuable tool to avoid malaria in travelers and in individuals living in endemic regions, estimated to be 2.5 billion exposed humans.